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Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition.

Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could f

Обобщение и оценка 6-ариламинобензамидов в качестве позитронных фотографических лигандов для рецептора фингозина-1-фосфата-5.

Спингосин-1-фосфат-5 (S1P5) является одним из пяти мембранных белковых рецепторов G, которые активируются лизофосфолипидом, фосфатом-1, что приводит к регулированию многих клеточных процессов. Рецепторы S1P5 расположены на олигодендроцитах и предлагаются для оказания влияния на физиологию олигодендроцитов. Понимание модуляции S1P5 в ходе таких процессов, как ремиелионация, может иметь потенциальные возможности для демиелионизации расстройств CNS, таких, как множественный склероз (MS). В этой связи мы сообщаем об обобщении и предварительной оценке серии фторированных 6-ариламинобензамидов в кач

Совпадение в аннотации оригинала
The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophosphol … ). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pil …

Comparative efficacy of taletrectinib versus first-generation TKIs in TKI-naïve ROS1+ non-small cell lung cancer: A matching-adjusted indirect comparison.

BACKGROUND: Taletrectinib is a next-generation, selective ROS1 tyrosine kinase inhibitor (TKI) approved for the treatment of advanced ROS1+ non-small cell lung cancer (NSCLC). In the absence of head-to-head trials comparing ROS1 TKIs, we aimed to compare the efficacy of taletrectinib with first-generation TKIs, crizotinib and entrectinib, in TKI-naïve patients with ROS1+ NSCLC using an unanchored matching-adjusted indirect comparison. METHODS: Selected baseline covariates were used for adjustment between pooled taletrectinib data from the TRUST-I (NCT04395677) and TRUST-II (NCT04919811) studi

ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.

Although androgen receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Me

Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis.

BACKGROUND: The progression of prostate cancer (PCa) to a castration-resistant state (CRPC) remains a major clinical challenge. Resistance to second-generation androgen receptor (AR) antagonists like enzalutamide often involves the reactivation of AR signaling, frequently through intratumoral androgen synthesis. The molecular drivers that regulate this adaptive resistance mechanism are not fully understood. GPR133 (also known as ADGRD1) is an adhesion G protein-coupled receptor with emerging roles in various cancers, but its function in prostate cancer is unknown. While androgen signaling is c

Real-world Comparative Study of Androgen Receptor Signaling Inhibitors in Japanese Patients With Non-metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Androgen receptor signaling inhibitors (ARSIs) are widely used for non-metastatic castration-resistant prostate cancer (nmCRPC). However, real-world data comparing clinical outcomes and treatment persistence among ARSIs in Asian populations remain limited. This study aimed to evaluate real-world effectiveness and tolerability of ARSIs in Japanese patients with nmCRPC. PATIENTS AND METHODS: We retrospectively reviewed 100 Japanese patients with nmCRPC treated with enzalutamide (ENZ), apalutamide (APA), or darolutamide (DARO) at Kansai Medical University and its affiliated hospi

Glutamate Ionotropic Kainate Receptors as Therapeutic Targets in Enzalutamide-Resistant and Neuroendocrine Prostate Cancer.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is the major form of resistance to androgen receptor signaling inhibitors (ARSI) in advanced prostate cancer, characterized by pronounced invasiveness and lineage plasticity. Through in-depth analysis of prostate cancer cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient-derived xenografts (PDX), and NEPC patient samples. Their expression positively correlates with neuroendocrine markers and in

Clinical Trial: Efficacy and Safety of Velusetrag in Chronic Intestinal Pseudo-Obstruction: A Randomized, Phase 2, Placebo-Controlled, Crossover, Multiple (n = 1), Proof-of-Concept Study.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare, severe disorder of gastrointestinal motility. Although 5-hydroxytryptamine type 4 (5-HT4) receptor agonists stimulate gastrointestinal motility, few trials have assessed their therapeutic effects in patients with CIPO. AIM: To assess the efficacy and safety of velusetrag, a highly selective 5-HT4 receptor agonist, in patients with CIPO. METHODS: This was a phase 2, placebo-controlled, crossover, multiple (n = 1), multicenter, double-blind, proof-of-concept trial. Eligible patients were aged 18-80 years, had CIPO (idiopathic

Cannabidiol alters the epigenome of hormone-dependent prostate cancer cells.

BACKGROUND: Cannabidiol (CBD) shows promising anti-cancer effects, including reducing proliferation and migration and inducing cell death. However, its impact on cancer gene regulation and epigenetic mechanisms remains poorly understood, particularly in prostate cancer, a disease characterised by widespread epigenetic alterations. PURPOSE: This study investigated whether CBD exerts anti-cancer effects in prostate cancer by modulating cell viability, gene expression, and the epigenome and whether it enhances the efficacy of targeted and hormonal agents. STUDY DESIGN/METHODS: Prostate cancer c

Final overall survival and safety analyses of the phase III PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer.

BACKGROUND: In PSMAfore, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC), with a favourable safety profile, versus a change in androgen receptor pathway inhibitor (ARPI). We report the final overall survival (OS) analysis and updated safety data. PATIENTS AND METHODS: PSMAfore (NCT04689828) was an open-label, international, phase III trial. Patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had experienced disease progression once on a previ

Efficacy and Safety of Combination Androgen-Receptor Signaling Inhibitors, Denosumab, and Local Radiotherapy for Poly-Metastatic Prostate Cancer.

BACKGROUND: The Treatment of Metastatic Castration-Sensitive Prostate Cancer (mCSPC) has dramatically changed over the past decade. To improve oncological outcomes, pharmacological treatments have evolved to include two-or three-drug combinations, and the efficacy of local radiation therapy (LRT) at the prostate combined with denosumab chemotherapy has been discussed. AIMS: This study aimed to provide an interim evaluation of the combination of androgen receptor signaling inhibitors denosumab, LRT, and metastasis-directed therapy (MDT) for prostate cancer with multiple bone metastases (poly-P

Preclinical Efficacy of TSL2109 in Prostate Cancer Treatment and Overcoming Enzalutamide Resistance.

Prostate cancer (PCa) is a highly prevalent and aggressive malignancy that poses a serious threat to men's health globally. Current treatments for PCa largely rely on hormone therapy; however, the development of drug resistance significantly diminishes its efficacy, highlighting the urgent need for novel therapeutic agents. Based on our prior work identifying dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) as a promising target in PCa, we developed a novel and potent DYRK2 inhibitor TSL2109, and resolved its cocrystal structure with DYRK2. TSL2109 exhibited high kinase sel

Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML.

PURPOSE: Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar). METHODS: We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older n

Tecovirimat for Clade I MPXV Infection in the Democratic Republic of Congo.

BACKGROUND: Tecovirimat is available for the treatment of mpox (formerly known as monkeypox) in Europe and the United States, on the basis of findings from efficacy studies in animals and safety evaluations in healthy humans. Evidence from randomized, controlled trials of safety and efficacy in patients with mpox is lacking. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of tecovirimat in patients with mpox in the Democratic Republic of Congo (DRC). Patients with at least one mpox skin lesion and positive polymerase-chain-reaction results for clade I MPXV were assi

Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine.

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibi

Investigating bleeding adverse events associated with BTK inhibitors in the food and drug administration adverse event reporting system (FAERS).

BACKGROUND: This study analyzed the bleeding adverse events (AEs) resulting from the treatment of B-cell lymphoma with Bruton tyrosine kinase (BTK) inhibitors, according to reports in the US Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Bleeding AEs associated with BTK inhibitors (including ibrutinib, zanubrutinib, and acalabrutinib) from the first quarter of 2013 to the third quarter of 2023 were extracted. Reporting odds ratio (ROR) and proportional reporting ratio (PRR) were reported. Preferred Terms (PTs) of Medical Dictionary for Regulatory Activities (M

Roflumilast Attenuates Microglial Senescence and Retinal Inflammatory Neurodegeneration Post Retinal Ischemia Reperfusion Injury Through Inhibiting NLRP3 Inflammasome.

PURPOSE: Retinal ischemia-reperfusion (RIR) injury is implicated in various retinal diseases, leading to retinal ganglion cells (RGCs) degeneration. Microglial senescence exacerbates inflammation, contributing to neurodegeneration. This study aimed to investigate the potential therapeutic role of Roflumilast (Roflu) in ameliorating microglial senescence and neuroinflammation following RIR injury. METHODS: C57BL/6J mice underwent RIR surgery, and Roflu treatment was administered intraperitoneally. BV2 microglial cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) to si

The protective effect of the vagus nerve-α7nAChR-IL-22 pathway on acute liver injury.

BACKGROUND: Acute liver injury is a common pathological feature of various clinical diseases, and prolonged liver damage can lead to fibrosis and even liver failure. Studies have reported that the vagus nerve can repair liver injury through the regulation of the cholinergic anti-inflammatory pathway. However, there is limited research on the regulation of interleukin-22 and its role in liver injury. This study aimed to investigate the regulatory effect of vagus nerve receptor α7nAChR on interleukin-22 and whether this regulatory axis can protect against liver injury. METHODS: Rats and the hum

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study.

BACKGROUND: Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax-obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions. METHODS: In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic